Hepatic metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the rat and guinea pig.
Hepatic metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the rat and guinea pig.
复制标题
大鼠和豚鼠体内 2,3,7,8-四氯二苯并-对二恶英 (TCDD) 的肝脏代谢。
DOI：
10.1016/0041-008x(85)90159-0
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发表时间：
1985
影响因子：
3.8
通讯作者：
Olson,JR
中科院分区：
文献类型：
--
作者：
Wroblewski,VJ;Olson,JR
2,3,7,8-四氯二苯并-对二恶英（TCDD）的急性毒性存在明显的种间差异，大鼠的LD50约为豚鼠的25倍。用纯化的[14C]TCDD （2.2 μm）孵育小鼠肝细胞8小时，检测TCDD的代谢。在8小时的孵育过程中，细胞色素P-450含量和乙氧基间苯甲酚o -去乙基化酶和苯丙胺n -去甲基化酶活性得到很好的维持，表明肝细胞具有功能活力。在[14C]TCDD代谢率上观察到定量差异，对照大鼠肝细胞代谢TCDD的速度是对照豚鼠肝细胞的2.8倍。肝细胞色素p -450-448依赖性单加氧酶系统在TCDD代谢中的作用通过使用TCDD （5 μg/kg, ip；分离前72小时）或苯巴比妥（80 mg/kg， ip × 3天；分离前24小时）预处理的动物肝细胞来检测。TCDD预处理豚鼠肝细胞中[14C]TCDD代谢物形成率（0.26±0.14 pmol mg细胞蛋白- 1hr−1）与对照组（0.25±0.07）相比没有变化，而TCDD预处理大鼠肝细胞中[14C]TCDD代谢物形成率（2.26±0.43 pmol mg - 1hr−1）是对照组（0.70±0.10）的3.2倍，是TCDD预处理豚鼠肝细胞的9倍。此外，在tcdd预处理的大鼠和豚鼠的肝细胞形成的代谢物谱中观察到显著差异。另一方面，苯巴比妥预处理对大鼠肝细胞[14C]TCDD代谢率变化不大（0.98±0.13 pmol mg−1hr−1）。这些结果表明TCDD可能被TCDD诱导的细胞色素P-448代谢，该细胞色素P-448在大鼠中表达，而在豚鼠中不表达。此外，TCDD在大鼠和豚鼠肝脏代谢的差异以及TCDD诱导自身代谢速率的能力可能是解释这些物种对TCDD急性毒性的不同易感性的主要原因。
Marked interspecies variability exists in the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), with the rat having an LD50 about 25-fold greater than the guinea pig. The metabolism of TCDD was examined by incubating hepatocytes isolated from these animals with purified [14C]TCDD (2.2 μm) for 8 hr. Over the 8-hr incubation, cytochrome P-450 content and ethoxyresorufin O-deethylase and benzphetamine N-demethylase activities were well maintained, indicating the functional viability of the hepatocytes. Quantitative differences were observed in the rate of [14C]TCDD metabolism, with hepatocytes from control rats metabolizing TCDD at a rate 2.8-fold greater than hepatocytes from control guinea pigs. The role of the hepatic cytochrome P-450-448-dependent monooxygenase system in the metabolism of TCDD was examined through the use of hepatocytes isolated from animals pretreated with either TCDD (5 μg/kg, ip; 72 hr prior to hepatocyte isolation) or phenobarbital (80 mg/kg, ip × 3 days; 24 hr prior to isolation). The rate of [14C]TCDD metabolite formation in hepatocytes from TCDD pretreated guinea pigs (0.26 ± 0.14 pmol mg cell protein−1hr−1) was unchanged from the control rate (0.25 ± 0.07), while the rate in hepatocytes from TCDD pretreated rats (2.26 ± 0.43 pmol mg−1hr−1) was 3.2-fold greater than control (0.70 ± 0.10) and nine times greater than in hepatocytes from TCDD-pretreated guinea pigs. In addition, significant differences were observed in the profiles of the metabolites formed by hepatocytes from TCDD-pretreated rats and guinea pigs. On the other hand, phenobarbital pretreatment produced little change in the rate of [14C]TCDD metabolism in rat hepatocytes (0.98 ± 0.13 pmol mg−1hr−1). These results suggest that TCDD may be metabolized by a TCDD inducible form of cytochrome P-448 which is expressed in the rat but not in the guinea pig. Furthermore, the differences in the hepatic metabolism of TCDD in the rat and guinea pig and in the ability of TCDD to induce its own rate of metabolism may play a major role in explaining the varying susceptibility of these species to the acute toxicity of TCDD.